Glycerol kinase deficiency. Clinical, biochemical, and genetic aspects

Abstract

Glycerol kinase deficiency (GKD, MIM 307030) is an X-linked recessive inborn error of metabolism occurring isolated or in an Xp contiguous gene syndrome with adrenal hypoplasia and/or Duchenne muscular dystrophy. The gene syndrome is due to deletions in the p21 region on the X chromosome. Children with deletions often present in early age with salt wasting and hypoglycaemia. Children with isolated GKD have hypoglycaemic symptoms with or without low blood glucose concentration and pronounced ketonemia in conjunction with infections or after physical exercise. The discrepancy between the severity of symptoms and the concurrent infection is of diagnostic value. Adult individuals with GKD have no similar symptoms. Individuals with GKD have a glycerol concentration of 2 to 8 mmol/L in plasma and excrete all glycerol from lipolysis into the urine (100-300 mmol/L, 10-30 g/24 h). Most triglyceride methods used in routine laboratories measure the amount of glycerol after hydrolysis and results in falsely reported elevated triglycerides in these patients. We have established methods to identify GKD as part of the Xp contiguous gene syndrome and an mRNA analysis to detect the glycerol kinase (GK) transcript from the Xp21 locus, enabling us to identify the genetic aberration. We have identified thirteen new mutations in the GK gene, used splice-junction analysis and molecular modelling to investigate the effect on the protein.The first individual (a 10-year-old boy) with symptoms from isolated GKD was described in 1983. We have followed him and another similar case into adulthood. Controlled fasting provocations and exercise tests were performed in childhood and repeated at adult age. We suggest that the greater importance of glycerol as a gluconeogenetic substrate in children than in adults, explains the hypoglycaemic episodes in the young GKD patient. With frequent carbohydrate-rich meals, carbohydrates with a low glycemic index, food or glucose when symptoms arise, extra food before and after physical activity, the prognosis is good.It is important to identify individuals at risk. Our studies have shown the need for a genetic analysis to distinguish between carriers and non-carriers, as the level of glycerol in plasma and urine or activity of GK can not discriminate.